The Lewis acidic properties of boronic acids, which derive from a vacant p-orbital, have been exploited for a variety of applications in reactions. Boronic acids are reported to have various biological and medicinal applications [Yang et al. 2005] and are of particular interest for saccharide chemosensing [James et al. 2005].
A variety of successful protecting group strategies have been developed to modulate undesired reactivity of boronic acids and allow for synthetic manipulation. A common example is the pinacol ester (illustrated in structure a below) which sterically shields the p-orbital from reaction. Similarly, Suginome and co-workers demonstrated the reduced reactivity of boronic acids when protected by 1,8-diaminonaphthalene (illustrated in structure b below) presumably due to electron delocalization of the nitrogen lone pairs onto the boron. [Noguchi et al. 2007; Noguchi et al. 2008] Another commonly employed strategy is based on the fluoro-affinity of boron to form trifluoroboronate salts (illustrated in structure c below) [Molander et al. 2011; Molander and Ellis 2007]. While highly stable, salts such as 5 are incompatible with chromatography, limiting their utility in multistep synthesis.

Burke and coworkers have popularized a three-coordinate N-methyliminodiacetic acid (MIDA) ligand for boronic acids that coordinates the vacant p-orbital with a trialkylamine to give a charge neutral adduct (6). [Gillis and Burke 2007; Gillis and Burke 2009; Knapp et al. 2009] The resulting complexes allow for broad compatibility with synthetic reagents and chromatographic purification. [Gillis and Burke 2008] U.S. Pat. Nos. 8,013,203, 8,318,983 and 8,338,601 relate to such three-coordinate iminodiacetic acid protecting groups and organoboronic acids protected by such protecting groups. The protected organoboronic acids are described as having a sp3 hybridized boron and a conformationally rigid protecting group bonded to the boron.
The protected organoboronic acids are described in the patent by the formula:
where R10 is an organic group, R20-24 are independently hydrogen or an organic group. MIDA is the species where R20 is a methyl group and R21-24 are all hydrogens.
Protecting groups for organoboronic acids are of particular interest for applications in Suzuki-Miyaura cross-coupling reactions [Miyaura and Suzuki 1995] between a boronic acid or ester and an organohalide or pseudo-halide. This coupling reaction is now widely used for the synthesis of complex organic molecules which involves the initial synthesis of chemically complex organoboronic acids or esters as reactants in the cross-coupling reaction. Because boronic acids react with many common reagents, synthesis of such complex organic boronic acid reactants is difficult and often requires introduction of the boronic acid group as the last step in the synthesis of the reactant.
Methods for introduction of the boronic acid group in addition may not be compatible with other common functional groups which enhances the complexity of syntheses of complex organoboronic reagents. The use of protecting groups for the boronic acid group which are tolerant to a wide range of reagents significantly reduces the complexity of synthesis of organoboronic acid reactants. Further, a protecting group must be removable by a method that does not detrimentally affect the functional groups on the organoboronic acid. In this regard, it is useful in the art to have various protecting groups which are removable by different means which may be more compatible for use with different organic functional groups.
Recent reports have emphasized the biological and therapeutic utility of oxaborole heterocyclic boronic acid variants called benzoxoboroles (also called benzoboroxoles). These variants have received increasing attention for applications in drug discovery, [Baker et al. 2009; Baker et al. 2011; Li et al. 2010; Rock et al. 2007; Obrecht et al. 2011; Qiao et al. 2012; Akama et al. 2009; Xia et al. 2011] synthetic methods, [Dixon et al. 2012] and biotechnology, [Ellis et al. 2012; Kim et al. 2012]. Benzoxaborole (1) [Adamczyk-Woźniaka 2009] in particular—characterized by a phenyl ring fused to a five-membered oxaborole—is perhaps the most widely employed oxaborole. The annulated benzylic alcohol in 1 appears to confer higher stability, [Snyder et al. 1958] lower pKa[Tomsho et al. 2012], and excellent sugar (diol) binding properties under physiological conditions (i.e., water, neutral pH) [Dowlut & Hall 2006; Berube et al. 2008; Tomsho and Benkovic 2012] compared to simple phenylboronic acid. However, the vacant p-orbital on boron—necessary for complexation with polyols—often complicates multistep syntheses of more complex derivatives.
Related compounds, benzoxaborins (2) have also been found to have biological and therapeutic applications, see International patent application WO2011116348.

Ellis et al. 2012 have recently reported the use of boronic acids, particularly phenyl boronic acids and benzoxoboroles to enhance cytosolic delivery of proteins. Protecting groups for organoboronic acids and benzoxoboroles would be of interest for the synthesis of new biological and therapeutically active compounds.
There is also interest in the preparation of peptides derivatized with organoboronic acids and boroxoles, [Pal et al. 2010]. Protecting groups for organoboronic acids, benzoxaboroles and benzoxaborins that are compatible with solid-phase peptide synthesis would thus be of interest in the art.
The divalent protecting groups (a and b) are not suitable for protection of benzoxaboroles (e.g., 1) or benzoxaborins (e.g., 2) because they would result in anionic boronate complexes. Likewise fluoride protection (c) would yield potassium difluoroborate salt. While MIDA is suitable for protection of organoboronic acids, it is trivalent and not suitable for protection of benzoxaboroles or benzoxaborins, which only have two coordination sites.
The present invention provides divalent protecting groups for the protection of benzoxaboroles and structurally related trivalent protecting groups for the protection of organoboronic acids, particularly for phenylboronic acids. These protecting groups generate neutral adducts which are stable to a broad range of basic conditions, but which are readily deprotected under aqueous acidic conditions. The stability properties of the protecting groups of this invention complement the MIDA protecting group that is stable to a broad range of acidic conditions, but cleave under aqueous basic conditions.